The development of small-molecule drugs that inhibit cell proliferation and angiogenesis (two key cellular processes needed for tumor growth) is prevalent. A particularly attractive target for small-molecule inhibition is the kinase c-Met, expression of which occurs in a wide variety of cell types where activation of the receptor induces cell migration, invasion, proliferation, and other biological activities associated with invasive cell growth. As such, signal transduction through c-Met receptor activation is responsible for many of the characteristics of tumor cells. Accordingly, the discovery of small-molecule inhibitors of c-Met is an ongoing challenge to the researcher.
Substituted quinolines have been reported to be promising for c-Met inhibition. For example, WO2005/030140 discloses a series of quinolinyloxydiphenylcyclopropanedicarboxamides, including N1-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-quinolinyl)oxy]phenyl}-N1-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide (illustrated), the preparation of which is described in Examples 25 (pp 193-194), 36 (pp 202-204), and 42-44 (pp 208-209) of the patent publication.
